hospitalization

Outpatient randomized controlled trials to reduce COVID-19 hospitalization: Systematic review and meta-analysis

Author/s: 
Daniele Focosi, David J. Sullivan, Daniel F. Hanley, Mario Cruciani, Massimo Franchini, Jiangda Ou, Arturo Casadevall, Nigel Paneth

This COVID-19 outpatient randomized controlled trials (RCTs) systematic review compares hospitalization outcomes amongst four treatment classes over pandemic period, geography, variants, and vaccine status. Outpatient RCTs with hospitalization endpoint were identified in Pubmed searches through May 2023, excluding RCTs <30 participants (PROSPERO-CRD42022369181). Risk of bias was extracted from COVID-19-NMA, with odds ratio utilized for pooled comparison. Searches identified 281 studies with 61 published RCTs for 33 diverse interventions analyzed. RCTs were largely unvaccinated cohorts with at least one COVID-19 hospitalization risk factor. Grouping by class, monoclonal antibodies (mAbs) (OR = 0.31 [95% CI = 0.24-0.40]) had highest hospital reduction efficacy, followed by COVID-19 convalescent plasma (CCP) (OR = 0.69 [95% CI = 0.53-0.90]), small molecule antivirals (OR = 0.78 [95% CI = 0.48-1.33]), and repurposed drugs (OR = 0.82 [95% CI: 0.72-0.93]). Earlier in disease onset interventions performed better than later. This meta-analysis allows approximate head-to-head comparisons of diverse outpatient interventions. Omicron sublineages (XBB and BQ.1.1) are resistant to mAbs Despite trial heterogeneity, this pooled comparison by intervention class indicated oral antivirals are the preferred outpatient treatment where available, but intravenous interventions from convalescent plasma to remdesivir are also effective and necessary in constrained medical resource settings or for acute and chronic COVID-19 in the immunocompromised.

Epley manoeuvre’s efficacy for benign paroxysmal positional vertigo (BPPV) in primary-care and subspecialty settings: a systematic review and meta-analysis

Author/s: 
Yusuke Saishoji, Norio Yamamoto, Takashi Fujiwara, Hideki Mori, Shunsuke Taito

Although previous studies have reported general inexperience with the Epley manoeuvre (EM) among general physicians, no report has evaluated the effect of EM on benign paroxysmal positional vertigo (BPPV) in primary care by using point estimates or certainty of evidence. We conducted this systematic review and meta-analysis and clarified the efficacy of EM for BPPV, regardless of primary-care and subspecialty settings.

Diagnosis and Management of Acute Left-Sided Colonic Diverticulitis: A Clinical Guideline From the American College of Physicians

Author/s: 
Qaseem, A., Etxeandia-Ikobaltzeta, I., Lin, J. S., Fitterman, N., Shamliyan, T., Wilt, T. J., Clinical Guidelines Committee of the American College of Physicians

Description: The American College of Physicians (ACP) developed this guideline to provide clinical recommendations on the diagnosis and management of acute left-sided colonic diverticulitis in adults. This guideline is based on current best available evidence about benefits and harms, taken in the context of costs and patient values and preferences.

Methods: The ACP Clinical Guidelines Committee (CGC) developed this guideline based on a systematic review on the use of computed tomography (CT) for the diagnosis of acute left-sided colonic diverticulitis and on management via hospitalization, antibiotic use, and interventional percutaneous abscess drainage. The systematic review evaluated outcomes that the CGC rated as critical or important. This guideline was developed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology.

Target audience and patient population: The target audience is all clinicians, and the target patient population is adults with suspected or known acute left-sided colonic diverticulitis.

Effect of Amoxicillin Dose and Treatment Duration on the Need for Antibiotic Re-treatment in Children With Community-Acquired Pneumonia: The CAP-IT Randomized Clinical Trial

Author/s: 
Bielicki, J. A., Stöhr, W., Barratt, S., Dunn, D., Naufal, N., Roland, D., Sturgeon, K., Finn, A., Rodriguez-Ruiz, J. P., Malhotra-Kumar, S., Powell, C., Faust, S. N., Alcock, A. E., Hall, D., Robinson, G., Hawcutt, D. B., Lyttle, M. D., Gibb, D. M., Sharland, M.

Importance
The optimal dose and duration of oral amoxicillin for children with community-acquired pneumonia (CAP) are unclear.

Objective
To determine whether lower-dose amoxicillin is noninferior to higher dose and whether 3-day treatment is noninferior to 7 days.

Design, Setting, and Participants
Multicenter, randomized, 2 × 2 factorial noninferiority trial enrolling 824 children, aged 6 months and older, with clinically diagnosed CAP, treated with amoxicillin on discharge from emergency departments and inpatient wards of 28 hospitals in the UK and 1 in Ireland between February 2017 and April 2019, with last trial visit on May 21, 2019.

Interventions
Children were randomized 1:1 to receive oral amoxicillin at a lower dose (35-50 mg/kg/d; n = 410) or higher dose (70-90 mg/kg/d; n = 404), for a shorter duration (3 days; n = 413) or a longer duration (7 days; n = 401).

Main Outcomes and Measures
The primary outcome was clinically indicated antibiotic re-treatment for respiratory infection within 28 days after randomization. The noninferiority margin was 8%. Secondary outcomes included severity/duration of 9 parent-reported CAP symptoms, 3 antibiotic-related adverse events, and phenotypic resistance in colonizing Streptococcus pneumoniae isolates.

Results
Of 824 participants randomized into 1 of the 4 groups, 814 received at least 1 dose of trial medication (median [IQR] age, 2.5 years [1.6-2.7]; 421 [52%] males and 393 [48%] females), and the primary outcome was available for 789 (97%). For lower vs higher dose, the primary outcome occurred in 12.6% with lower dose vs 12.4% with higher dose (difference, 0.2% [1-sided 95% CI –∞ to 4.0%]), and in 12.5% with 3-day treatment vs 12.5% with 7-day treatment (difference, 0.1% [1-sided 95% CI –∞ to 3.9]). Both groups demonstrated noninferiority with no significant interaction between dose and duration (P = .63). Of the 14 prespecified secondary end points, the only significant differences were 3-day vs 7-day treatment for cough duration (median 12 days vs 10 days; hazard ratio [HR], 1.2 [95% CI, 1.0 to 1.4]; P = .04) and sleep disturbed by cough (median, 4 days vs 4 days; HR, 1.2 [95% CI, 1.0 to 1.4]; P = .03). Among the subgroup of children with severe CAP, the primary end point occurred in 17.3% of lower-dose recipients vs 13.5% of higher-dose recipients (difference, 3.8% [1-sided 95% CI, –∞ to10%]; P value for interaction = .18) and in 16.0% with 3-day treatment vs 14.8% with 7-day treatment (difference, 1.2% [1-sided 95% CI, –∞ to 7.4%]; P value for interaction = .73).

Conclusions and Relevance
Among children with CAP discharged from an emergency department or hospital ward (within 48 hours), lower-dose outpatient oral amoxicillin was noninferior to higher dose, and 3-day duration was noninferior to 7 days, with regard to need for antibiotic re-treatment. However, disease severity, treatment setting, prior antibiotics received, and acceptability of the noninferiority margin require consideration when interpreting the findings.

Trial Registration
ISRCTN Identifier: ISRCTN76888927

Efficacy and Safety of Nonantibiotic Outpatient Treatment in Mild Acute Diverticulitis (DINAMO-study): A Multicentre, Randomised, Open-label, Noninferiority Trial

Author/s: 
Mora-López, L., Ruiz-Edo, N., Estrada-Ferrer, O., Piñana-Campón, M. L., Labró-Ciurans, M., Escuder-Perez, J., Sales-Mallafré, R., Rebasa-Cladera, P., Navarro-Soto, S., Serra-Aracil, X.

Objective:
Mild AD can be treated safely and effectively on an outpatient basis without antibiotics.

Summary of Background Data:
In recent years, it has shown no benefit of antibiotics in the treatment of uncomplicated AD in hospitalized patients. Also, outpatient treatment of uncomplicated AD has been shown to be safe and effective.

Methods:
A Prospective, multicentre, open-label, noninferiority, randomized controlled trial, in 15 hospitals of patients consulting the emergency department with symptoms compatible with AD.

The Participants were patients with mild AD diagnosed by Computed Tomography meeting the inclusion criteria were randomly assigned to control arm (ATB-Group): classical treatment (875/125 mg/8 h amoxicillin/clavulanic acid apart from anti-inflammatory and symptomatic treatment) or experimental arm (Non-ATB-Group): experimental treatment (antiinflammatory and symptomatic treatment). Clinical controls were performed at 2, 7, 30, and 90 days.

The primary endpoint was hospital admission. Secondary endpoints included number of emergency department revisits, pain control and emergency surgery in the different arms.

Results:
Four hundred and eighty patients meeting the inclusion criteria were randomly assigned to Non-ATB-Group (n = 242) or ATB-Group (n = 238). Hospitalization rates were: ATB-Group 14/238 (5.8%) and Non-ATB-Group 8/242 (3.3%) [mean difference 2.58%, 95% confidence interval (CI) 6.32 to -1.17], confirming noninferiority margin. Revisits: ATB-Group 16/238 (6.7%) and Non-ATB-Group 17/242 (7%) (mean difference -0.3, 95% CI 4.22 to -4.83). Poor pain control at 2 days follow up: ATB-Group 13/230 (5.7%), Non-ATB-Group 5/221 (2.3%) (mean difference 3.39, 95% CI 6.96 to -0.18).

Conclusions:
Nonantibiotic outpatient treatment of mild AD is safe and effective and is not inferior to current standard treatment.

Trial registration:
ClinicalTrials.gov (NCT02785549); EU Clinical Trials Register (2016-001596-75)

Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices, United States, 2021-22 Influenza Season

Author/s: 
Grohskopf, L. A., Alyanak, E., Ferdinands, J. M., Broder, K. R., Blanton, L. H., Talbot, H. K., Fry, A. M.

This report updates the 2020–21 recommendations of the Advisory Committee on Immunization Practices (ACIP) regarding the use of seasonal influenza vaccines in the United States (MMWR Recomm Rep 2020;69[No. RR-8]). Routine annual influenza vaccination is recommended for all persons aged ≥6 months who do not have contraindications. For each recipient, a licensed and age-appropriate vaccine should be used. ACIP makes no preferential recommendation for a specific vaccine when more than one licensed, recommended, and age-appropriate vaccine is available. During the 2021–22 influenza season, the following types of vaccines are expected to be available: inactivated influenza vaccines (IIV4s), recombinant influenza vaccine (RIV4), and live attenuated influenza vaccine (LAIV4).

The 2021–22 influenza season is expected to coincide with continued circulation of SARS-CoV-2, the virus that causes COVID-19. Influenza vaccination of persons aged ≥6 months to reduce prevalence of illness caused by influenza will reduce symptoms that might be confused with those of COVID-19. Prevention of and reduction in the severity of influenza illness and reduction of outpatient visits, hospitalizations, and intensive care unit admissions through influenza vaccination also could alleviate stress on the U.S. health care system. Guidance for vaccine planning during the pandemic is available at https://www.cdc.gov/vaccines/pandemic-guidance/index.html. Recommendations for the use of COVID-19 vaccines are available at https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/covid-19.html, and additional clinical guidance is available at https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-v....

Updates described in this report reflect discussions during public meetings of ACIP that were held on October 28, 2020; February 25, 2021; and June 24, 2021. Primary updates to this report include the following six items. First, all seasonal influenza vaccines available in the United States for the 2021–22 season are expected to be quadrivalent. Second, the composition of 2021–22 U.S. influenza vaccines includes updates to the influenza A(H1N1)pdm09 and influenza A(H3N2) components. U.S.-licensed influenza vaccines will contain hemagglutinin derived from an influenza A/Victoria/2570/2019 (H1N1)pdm09-like virus (for egg-based vaccines) or an influenza A/Wisconsin/588/2019 (H1N1)pdm09-like virus (for cell culture–based and recombinant vaccines), an influenza A/Cambodia/e0826360/2020 (H3N2)-like virus, an influenza B/Washington/02/2019 (Victoria lineage)-like virus, and an influenza B/Phuket/3073/2013 (Yamagata lineage)-like virus. Third, the approved age indication for the cell culture–based inactivated influenza vaccine, Flucelvax Quadrivalent (ccIIV4), has been expanded from ages ≥4 years to ages ≥2 years. Fourth, discussion of administration of influenza vaccines with other vaccines includes considerations for coadministration of influenza vaccines and COVID-19 vaccines. Providers should also consult current ACIP COVID-19 vaccine recommendations and CDC guidance concerning coadministration of these vaccines with influenza vaccines. Vaccines that are given at the same time should be administered in separate anatomic sites. Fifth, guidance concerning timing of influenza vaccination now states that vaccination soon after vaccine becomes available can be considered for pregnant women in the third trimester. As previously recommended, children who need 2 doses (children aged 6 months through 8 years who have never received influenza vaccine or who have not previously received a lifetime total of ≥2 doses) should receive their first dose as soon as possible after vaccine becomes available to allow the second dose (which must be administered ≥4 weeks later) to be received by the end of October. For nonpregnant adults, vaccination in July and August should be avoided unless there is concern that later vaccination might not be possible. Sixth, contraindications and precautions to the use of ccIIV4 and RIV4 have been modified, specifically with regard to persons with a history of severe allergic reaction (e.g., anaphylaxis) to an influenza vaccine. A history of a severe allergic reaction to a previous dose of any egg-based IIV, LAIV, or RIV of any valency is a precaution to use of ccIIV4. A history of a severe allergic reaction to a previous dose of any egg-based IIV, ccIIV, or LAIV of any valency is a precaution to use of RIV4. Use of ccIIV4 and RIV4 in such instances should occur in an inpatient or outpatient medical setting under supervision of a provider who can recognize and manage a severe allergic reaction; providers can also consider consulting with an allergist to help identify the vaccine component responsible for the reaction. For ccIIV4, history of a severe allergic reaction (e.g., anaphylaxis) to any ccIIV of any valency or any component of ccIIV4 is a contraindication to future use of ccIIV4. For RIV4, history of a severe allergic reaction (e.g., anaphylaxis) to any RIV of any valency or any component of RIV4 is a contraindication to future use of RIV4.

This report focuses on recommendations for the use of vaccines for the prevention and control of seasonal influenza during the 2021–22 influenza season in the United States. A brief summary of the recommendations and a link to the most recent Background Document containing additional information are available at https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/flu.html. These recommendations apply to U.S.-licensed influenza vaccines used according to Food and Drug Administration–licensed indications. Updates and other information are available from CDC’s influenza website (https://www.cdc.gov/flu); vaccination and health care providers should check this site periodically for additional information.

Association Between Age and Complications After Outpatient Colonoscopy

Author/s: 
Causada-Calo, N., Bishay, K., Albashir, S., Mazroui, A.A., Armstrong, D.

Abstract

Importance: There are insufficient data describing the incidence and risk factors of postcolonoscopy complications in older individuals.

Objective: To assess the association between older age (≥75 years) and the risk of postcolonoscopy complications.

Design, setting, and participants: This population-based retrospective cohort study included adults (≥50 years) undergoing outpatient colonoscopy between April 2008 and September 2017, identified from Ontario administrative databases. Individuals with inflammatory bowel disease and hereditary colorectal cancer syndromes were excluded. The study population was subdivided into a colorectal cancer screening-eligible cohort (patients aged 50-74 years) and an older cohort (patients aged ≥75 years). The statistical analysis was conducted from December 2018 to September 2019.

Exposures: Older age (≥75 years).

Main outcomes and measures: The primary outcome was postcolonoscopy complications, defined as the composite of hospitalization or emergency department visits in the 30-day period after the outpatient colonoscopy. Secondary outcomes included incidence of surgically treated colorectal cancer and all-cause mortality at 30 days. Independent variables associated with postcolonoscopy complications were also assessed.

Results: The study sample included 38 069 patients; the mean (SD) age was 65.2 (10.1) years, there were 19 037 women (50.0%), and 27 831 patients (73.1%) underwent a first colonoscopy. The cumulative incidence of complications was 3.4% (1310 patients) in the overall population, and it was higher in individuals aged 75 years or older (515 of 7627 patients [6.8%]) than in screening-eligible cohort (795 of 30 443 patients [2.6%]) (P < .001). Independent risk factors for postcolonoscopy complications were age 75 years or older (odds ratio [OR], 2.3; 95% CI, 2.0-2.6), anemia (OR, 1.4; 95% CI, 1.2-1.7), cardiac arrhythmia (OR, 1.7; 95% CI, 1.2-2.2), congestive heart failure (OR, 3.4; 95% CI, 2.5-4.6), hypertension (OR, 1.2; 95% CI, 1.0-1.5), chronic kidney disease (OR, 1.8; 95% CI, 1.1-3.0), liver disease (OR, 4.7; 95% CI, 3.5-6.5), smoking history (OR, 3.2; 95% CI, 2.4-4.3), and obesity (OR, 2.3; 95% CI, 1.2-4.2). The number of previous colonoscopies was associated with a lower risk of complications (OR, 0.9; 95% CI, 0.7-1.0). The incidence of surgically treated colorectal cancer was higher in the older cohort than the screening-eligible cohort (119 patients [1.6%] vs 144 patients [0.5%]; P < .001). All-cause mortality rates were 0.1% overall (39 patients) and 0.1% (19 patients) for individuals aged 50 to 74 years and 0.2% (20 patients) for those aged 75 years and older (P < .001).

Conclusions and relevance: In this population-based cohort study of individuals living in southern Ontario, age of 75 years and older was associated with a higher risk of 30-day postprocedure complications after outpatient colonoscopy. These findings suggest that the decision to perform a colonoscopy should be carefully considered in patients older than 75 years, especially in the presence of comorbidities. Further studies are needed to better understand the benefits of invasive procedures as opposed to less invasive approaches for colorectal cancer screening and surveillance among older patients.

Effectiveness of a Mouth Care Program Provided by Nursing Home Staff vs Standard Care on Reducing Pneumonia Incidence: A Cluster Randomized Trial

Author/s: 
Zimmerman, S., Sloane, P.D., Ward, K., Wretman, C.J., Stearns, S.C., Poole, P., Preisser, J.S.

Abstract

Importance: Pneumonia affects more than 250 000 nursing home (NH) residents annually. A strategy to reduce pneumonia is to provide daily mouth care, especially to residents with dementia.

Objective: To evaluate the effectiveness of Mouth Care Without a Battle, a program that increases staff knowledge and attitudes regarding oral hygiene, changes mouth care, and improves oral hygiene, in reducing the incidence of pneumonia among NH residents.

Design, setting, and participants: This pragmatic cluster randomized trial observing 2152 NH residents for up to 2 years was conducted from September 2014 to May 2017. Data collectors were masked to study group. The study included 14 NHs from regions of North Carolina that evidenced proportionately high rehospitalization rates for pneumonia and long-term care residents. Nursing homes were pair matched and randomly assigned to intervention or control groups.

Intervention: Mouth Care Without a Battle is a standardized program that teaches that mouth care is health care, provides instruction on individualized techniques and products for mouth care, and trains caregivers to provide care to residents who are resistant and in special situations. The control condition was standard mouth care.

Main outcomes and measures: Pneumonia incidence (primary) and hospitalization and mortality (secondary), obtained from medical records.

Results: Overall, the study enrolled 2152 residents (mean [SD] age, 79.4 [12.4] years; 1281 [66.2%] women; 1180 [62.2%] white residents). Participants included 1219 residents (56.6%) in 7 intervention NHs and 933 residents (43.4%) in 7 control NHs. During the 2-year study period, the incidence rate of pneumonia per 1000 resident-days was 0.67 and 0.72 in the intervention and control NHs, respectively. Neither the primary (unadjusted) nor secondary (covariate-adjusted) analyses found a significant reduction in pneumonia due to Mouth Care Without a Battle during 2 years (unadjusted incidence rate ratio, 0.90; upper bound of 1-sided 95% CI, 1.24; P = .27; adjusted incidence rate ratio, 0.92; upper bound of 1-sided 95% CI, 1.27; P = .30). In the second year, the rate of pneumonia was nonsignificantly higher in intervention NHs. Adjusted post hoc analyses limited to the first year found a significant reduction in pneumonia incidence in intervention NHs (IRR, 0.69; upper bound of 1-sided 95% CI, 0.94; P = .03).

Conclusions and relevance: This matched-pairs cluster randomized trial of a mouth care program compared with standard care was not effective in reducing pneumonia incidence at 2 years, although reduction was found during the first year. The lack of significant results in the second year may be associated with sustainability. Improving mouth care in US NHs may require the presence and support of dedicated oral care aides.

Initial Invasive or Conservative Strategy for Stable Coronary Disease

Author/s: 
Maron, DJ, Hochman, JS, Reynolds, HR, Bangalore, S, O'Brien, SM, Boden, WE, Chaitman, BR, Senior, R, Lopez-Sendon, J, Alexander, KP, Lopes, RD, Shaw, LJ, Berger, JS, Newman, JD, Sidhu, MS, Goodman, SG, Ruzyllo, W, Gosselin, G, Maggioni, AP, White, HD, Bhargava, B, Min, JK, Mancini, GBJ, Berman, DS, Picard, MH, Kwong, RY, Ali, ZA, Mark, DB, Spertus, JA, Krishnan, MN, Elghamaz, A, Moorthy, N, Hueb, WA, Demkow, M, Mavromatis, K, Bockeria, O, Peteiro, J, Miller, TD, Szwed, H, Doerr, R, Keltai, M, Selvanayagam, JB, Steg, PG, Held, C, Kohsaka, S, Mavromichalis, S, Kirby, R, Jeffries, NO, Harrell, FE Jr, Rockhold, FW, Broderick, S, Ferguson, TB Jr, Williams, DO, Harrington, RA, Stone, GW, Rosenberg, Y, ISCHEMIA Research Group

Background: Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain.

Methods: We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction.

Results: Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, -1.8 percentage points; 95% CI, -4.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32).

Conclusions: Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA ClinicalTrials.gov number, NCT01471522.).

Meta-Analysis Evaluating the Effects of Renin-Angiotensin-Aldosterone System Blockade on Outcomes of Heart Failure With Preserved Ejection Fraction

Author/s: 
Kuno, T, Ueyama, H, Fujisaki, T, Briasouli, A, Takagi, H, Briasoulis, A

Clinical trials of renin-angiotensin-aldosterone system (RAAS) antagonists in heart failure with preserved ejection fraction (HFpEF) have suggested neutral results and treatment is focused on associated symptoms and comorbidities. MEDLINE and EMBASE were searched through October 2019 for randomized controlled studies investigating the effects of different RAAS antagonists in patients with HFpEF. The main outcomes were all-cause mortality, trial defined cardiovascular mortality, and heart failure (HF) hospitalizations. To compare different RAAS antagonists, a random-effects restricted-maximum-likelihood network meta-analysis based on a frequentist framework for indirect and mixed comparisons was used. We used p scores to rank best treatments per outcome. Our search identified 5 eligible clinical trials (PEP-CHF, perindopril; CHARM-preserved, candesartan; I-PRESERVE, irbesartan; TOPCAT, spironolactone; PARAGON-HF, sacubitril-valsartan and valsartan) enrolling a total 10,523 on RAAS antagonists and 6,259 controls. We did not identify any statistical difference in all-cause and cardiovascular mortality among RAAS antagonists and placebo. The combination of sacubitril-valsartan was associated with significantly decreased HF hospitalization risk compared with controls (odds ratio 0.73, 95% confidence interval 0.61 to 0.87) and angiotensin II receptor blockers (odds ratio 0.80, 95% confidence interval 0.71 to 0.91), without heterogeneity among studies (I2 = 0). Angiotensin receptor neprilysin inhibitor (ARNI) ranked better than other RAAS antagonists for HF hospitalizations (p value 0.9). In conclusion, RAAS antagonists do not affect mortality but the combination of sacubitril-valsartan is associated with lower HF hospitalizations in HFpEF patients.

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